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Journal of Clinical Neuroscience (2002) 9(6), 613±617
& 2002 Published by Elsevier Science Ltd.
DOI: 10.1054/jocn.2002.1080, available online at http://www.idealibrary.com on
Review
Current concepts in central nervous system
regeneration
Ross D. Gurgo1 MBBS, Kuldip S. Bedi2 PHD DSC, Victor Nurcombe2 PHD
1
Department of Neurosurgery, Princess Alexandra Hospital, Brisbane, 2Department of Anatomy and Developmental Biology,
The University of Queensland, Australia
Summary A dictum long-held has stated that the adult mammalian brain and spinal cord are not capable of regeneration after injury.
Recent discoveries have, however, challenged this dogma. In particular, a more complete understanding of developmental neurobiology
has provided an insight into possible ways in which neuronal regeneration in the central nervous system may be encouraged. Knowledge of
the role of neurotrophic factors has provided one set of strategies which may be useful in enhancing CNS regeneration. These factors can
now even be delivered to injury sites by transplantation of genetically modified cells. Another strategy showing great promise is the discovery and isolation of neural stem cells from adult CNS tissue. It may become possible to grow such cells in the laboratory and use these
to replace injured or dead neurons. The biological and cellular basis of neural injury is of special importance to neurosurgery, particularly as
therapeutic options to treat a variety of CNS diseases becomes greater. & 2002 Published by Elsevier Science Ltd.
Keywords: neural, regeneration, neurobiology, neurotrophins, stem cells, transplantation
INTRODUCTION
Unlike most other systems, the central nervous system has a
limited capacity for regeneration, making any injury particularly devastating. Ramon y Cajal reported in 1928 that injured
CNS axons could re-grow into pre-degenerated peripheral
nerve tissue.1 This was later confirmed by Aguayo's group in
the 1980s.2 These researchers went on to show that the CNS
neurons were intrinsically able to regenerate their injured
axons if exposed to suitable environmental conditions. Over
the past decade much work has focused on understanding the
cellular and molecular bases of this axonal regeneration. These
studies may have application for the treatment of traumatic
injuries of the spinal cord and brain. In parallel to these studies
a greater understanding of the factors which cause neuronal
cell death in the CNS may open up the possibility of enhancing
neuronal survival after injury or during degenerative diseases
of the nervous system (such as Parkinson's disease or motor
neuron disease).
Regeneration within the CNS is a multistep process. In
order to achieve neuronal regeneration after injury, several
factors have to be controlled. First, the injured neurons have to
survive or be replaced by newly transplanted neurons. The
axons of these neurons must be induced to re-grow and find a
pathway to the appropriate targets. The axon terminals are
required to form functional synaptic contacts with the correct
regions of the targets. Only once all of these conditions have
been met is it possible to restore correct functioning of the
injured region. Prevention of neuronal cell death after injury is
the subject of much current research. Axon growth occurs at
the growth cone, which itself is responsive to the external
environment. There are known to be factors in the post-lesion
CNS environment that can either inhibit or augment growth
cone activity. These factors operate via cell surface receptors
which when activated cause a cascade of events via intracellular messengers that eventually involve changes in the cytoskeleton. These changes are capable of controlling and directing
axonal growth. It is important to appreciate that clinical
neurological improvement after injury is not necessarily evidence of axonal regeneration. Often it is possible to explain
such improvement as being the result of other mechanisms that
may involve the recruitment of other pre-existing pathways to
take over the functions of an injured pathway.
CONTRIBUTION OF DEVELOPMENTAL
NEUROBIOLOGY TO THE UNDERSTANDING OF
NEURAL REGENERATION
A thorough knowledge of how embryonic neural cells first
arise in development from a pool of uncommitted precursors
and develop into mature neurons may enhance our ability in
understanding neuronal regeneration. It may also show us how
transplanted cells may survive, grow and integrate themselves
into a host CNS. Our increasing understanding of genomics
and stem cell biology has presented us a multitude of genes and
gene products that may have crucial roles in neuronal survival
and regeneration. It is now known that the extracellular
environment, largely created by cellular exudates, is part of a
crucial feedback loop. This influences the cell nucleus as to the
order of genes that need to be sequentially activated during the
developmental cascades. The discipline of developmental
neurobiology has identified the inductive interactions that give
rise to different neuronal subtypes ± and seeks to explain them
in molecular terms. In contrast, neural stem cell biology has
concerned itself with the lineage relationships between cells
and how they make choices regarding differentiation.3
Received 5 October 2001
Accepted 22 January 2002
NEUROTROPHIC FACTORS
Correspondence to: Dr Ross D. Gurgo, Department of Neurosurgery, Princess
Alexandra Hospital, Ipswich Road, Woolloongabba Queensland 4102,
Australia. E-mail: [email protected]
Any review of CNS regeneration is not complete without
mention of the neuronal-growth/supportive role of neurotrophic factors. A family of polypeptides, collectively known
613
614 Gurgo et al.
as neurotrophins, which include the prototypical NGF, as well
as BDNF, NT3, NT4/5 and NT6, are believed to be at least
partially responsible for keeping developing neurons viable
until their projecting axons and dendrites reach their target
tissue.4 Thus, a neurotrophic factor has a neurotrophic function, in addition to its neurotropic role, axon guidance.5 Since
the distance axons are required to grow varies between
populations of neurons, the timing of specific neurotrophic
dependencies also varies accordingly. It has been postulated
that neurons are programmed before differentiation to switch
chemotrophic dependencies at the right time, irrespective
of external signals.6 This can also be demonstrated in vitro
(Figs 1, 2). Neurotrophins are not only restricted to the
survival of differentiated neurons, they have also been shown
to promote differentiation during neural development.7
Neurotrophic activity may be in part dependent on other more
mitogenic factors, such as heparin sulphate proteoglycans.8
This mechanism allows tissue and temporally-specific regulation of the neurotrophic factor effect and thus may provide
an sopportunity for clinical manipulation. Neurotrophic factors, aside from their actions during CNS development, also
have a role in `day-to-day' maintenance of CNS integrity.
Fig. 1 Nerve Cells being grown in in vitro cell culture (upper photo) and
staining with neuronal-specific staining to indicate neuronal (as opposed to
glial) differentiation (lower photo).
Journal of Clinical Neuroscience (2002) 9(6), 613±617
Implantation of cells genetically engineered to produce
neurotrophic factors may therefore be important in promoting
CNS regeneration; however, the optimal way of achieving this
has not yet been determined.
THE USE OF STEM CELLS IN
NEURAL REGENERATION
Although much is known about the embryonic development of
the brain, the lineages that neural precursors follow during
brain growth and their continued role in adult life are only
partly understood. Until recently, it was unclear whether
neurogenesis proceeded like haematopoiesis ± from a pluripotent batch of stem cells that both self-renew and produce
multipotent progenitors that give rise to progressively more
committed progeny, or if some other developmental hierarchy
was present.9 Recent in vitro studies indicate that multipotent,
Fig. 2 Cellular differentiation from a neurosphere (undifferentiated cells).
Neurla progenitor cells with differentiate into glial cells (upper photo) unless
cultured in a medium containing FGF-1, which will cause them to differentiate
into neurons (lower photo).
& 2002 Published by Elsevier Science Ltd.
Current concepts in CNS regeneration 615
self-renewing progenitors of neurons and glia can be isolated
from adult brain regions.10 The demonstration that the adult
brain contains stem cells raises the attractive possibility that
endogenous neurogenesis may be manipulated to therapeutic
advantage11 after CNS injury. DNA labelling studies have
shown that progenitors residing in the subventricular zones
adjacent to the ependyma continuously migrate to the olfactory bulb and differentiate into local interneurons.12 Similarly,
in the adult hippocampus, progenitors in the subgranular zone
have been shown to give rise to cells that differentiate into
dentate gyrus granule cells.13 Moreover, the cells seem to be
remarkably plastic: adult hippocampal stem cells can give rise
to regionally-specific cell types not only in the hippocampus,
but also in the olfactory bulb, cerebellum, and retina.14,15 They
can even migrate considerable distances, especially after
implantation into the neonatal brain.16 Thus, neural stem cells
from both embryo and adult seem to be `re-programmable'; an
idea, drawn from haematopoeisis, that there is a generic,
`naõÈ ve' brain stem cell. What is proving truly remarkable is the
range of cell types that can be produced in a culture dish when
the environment ± growth or trophic factors, in combination
with particular substrates ± is configured appropriately. In
the CNS of the developing embryo the process of neuronal
subtype development is dependent on the three-dimensional
patterning of the developing neural tube. CNS neuronal specification is now thought to occur within a 3-dimensional
coordinate system of inductive signals.17 This produces
neuronal subtype specification. The differentiation of dopaminergic neurons occurs much more robustly in threedimensional explant cultures of intact embryonic brain than in
single cell culture.18
The contribution of developmental neurobiology to
understanding neuronal regeneration and implications for
CNS cellular transplantation is clear. There may exist neuronal
`stem' cells in the adult CNS that may be cultured and used for
CNS repair. If transplantation of cells into the CNS is to
continue to progress, lessons from the developing CNS, such
as the way in which a developing cell `integrates' into its
surrounding environment in a three-dimensional context and
the factors which support this occurrence, must be applied.
MEDIATORS OF NEURONAL CELL DEATH
Compared to other cell types, neurons seem to have evolved
quite a complex death mechanism. Unlike most other cells,
which are quickly turned over, neurons are postmitotic ±
throughout our lives, we maintain roughly the same set of
neurons as when we are born. Thus, the CNS seems to have
adapted an entirely different defence for neurons aimed at
keeping them alive as long as possible. How does knowledge
of this complicated set of mechanisms help us as for the
treatment of neurodegenerative disorders? It is now known
that apoptotic mechanisms contribute to both acute and
chronic neurodegenerative diseases.19 The multiple controlling
points in the neuronal death pathways provide a large number
of possibilities at which to intercede therapeutically. That is,
to prevent cell death and stimulate regeneration the intracellular signals that transduce external insults may be altered.
Apoptotic cell death is controlled by several transcription
factors (p53, fas, c-Jun, bax and bcl-2) that may be manipulated pharmacologically or genetically in order to prevent such
cell loss.20 The upregulation of anti-apoptotic genes may
also be pro-regenerative. Manipulation of growth-associated
proteins such as tubulin, actin and GAP-43 may stimulate a
cell to re-enter a regenerative mode. Intracellular calcium and
& 2002 Published by Elsevier Science Ltd.
second messengers (cAMP, cGMP) also offer means for
intervention due to their transducive roles. However, effects
observed in in vitro experiments can be difficult to replicate in
the in vivo situation. Various drugs which have the intention to
manipulate a certain biochemical pathway may be lethal when
administered systemically in humans. Furthermore, systemic
approaches by their very nature affect all regions of the body
and do not allow for cell type individuality and uniqueness of
response within the CNS. The response of cells to neurotrophic
factors may be altered after injury or encountering an inhibitory substrate.21 Concepts of neuroprotection, well documented in the neurosurgical literature, will complement other
concepts, as just described, to prevent neuronal death in a
clinical setting.
AXON GUIDANCE AND REMOVAL OF
GROWTH INHIBITION
In addition to axonal regeneration, correct axon guidance and
synapse formation is required for functional recovery. A
number of axon guidance molecules exist, such as polysialic
acid-containing neural adhesion molecules (NCAMs) which
have been shown to be associated with regenerating axons in
the hippocampus. Other proteins, such as the SLIT group,
also act to guide axons during development although their
role following neuronal damage is not well understood.
Growth inhibitory molecules were first systematically documented by Schwab's group in 1988,22 which discovered an
antibody (INO-1) which could block inhibitory effects of glial
scars on axonal regeneration. This inhibitory target has
now been cloned ± NOGO.23 An understanding of developmental neurobiology and the role of axonal guidance
molecules has heightened the understanding of the way in
which neurons respond to insult. Some of the inhibitory factors expressed during CNS development may be re-expressed
after CNS injury, such as the chemorepellant semaphorin III24
and the proteoglycan NG2.25 Scar tissue, rich in the sugar
chondroitin sulfate, may act as a simple barrier to axon
regrowth,26 tested by the use of the enzyme chondroitinase
against this component.27 Chondroitin sulfate may also induce
or enhance immune response after neurotrauma (or indeed
transplantation procedures) and so discourage axon growth.
Post-traumatic cellular responses, in particular macrophage
and microglial activation, may inhibit axon regrowth.28 In fact,
when glial scarring has been experimentally reduced, axonal
regrowth is significantly enhanced.29 It is clear, however, that
axon guidance molecules, both permissive and inhibitory, have
the potential to be manipulated to circumvent scar tissue
and promote axon growth.
CLINICAL APPLICATIONS
Cell replacement is an important step in CNS recovery because
of the limited regenerative and divisional capacity.30±36 The
first step to a successful graft is survival and the second the
formation of the required neuronal connections. If stem cells
are used, appropriate differentiation into the required cell must
occur. Co-implantation of cells which have been genetically
engineered to produce neurotrophic factors may enhance
stem cell survival.37 Recent research has demonstrated that
there stem cells exist in the CNS, mainly the hippocampus
and possibly the subventricular zone; such cells could be used
as a source of stem cells for reimplantation.3 Fetal cells
represent the ideal source of stem cells due to their plasticity
Journal of Clinical Neuroscience (2002) 9(6), 613±617
616 Gurgo et al.
(pluripotentiality) and relative lack of immune excitation;
however, ethical and political issues have impeded their use.
`Immortalised' neurons from culture have also been used
experimentally, such as the NT2 (human terato-carcinomainitiated neuronal cell line38 and have shown both prolonged
survivability after transplantation and, importantly, appropriate integration into local neural circuits. Demyelinating
diseases may also be treated by cellular replacement; oligodendrocyte/type 2 astrocyte progenitor cells have been shown
to be capable of extensive remyelination when injected into
the CNS.39
Cell grafts which have been engineered to produce neurotrophic factors (such as NT3, BDNF, CDNF) also hold
promise for axonal regeneration and neuronal recovery.
Aguayo has shown that Muller cells engineered to produce
BDNF may temporarily rescue injured retinal ganglion cells.40
Fibroblasts engineered to express BDNF have also been shown
to promote long-tract regeneration in the spinal cord.41
Various studies have only shown adequate regeneration in the
milieu of the growth factors and not beyond.42 The temporary
response has been attributed to growth-inhibitory effects
induced by the lesion.40 Intrathecal administration of neurotrophic factors has been suggested for a more widespread
response.43 A more complete understanding of the widespread
effects of neurotrophins on neuronal function, beyond regeneration on neuronal activity (such as membrane excitability) is
required before their optimal use in a clinical setting can be
achieved. The use of genetically engineered cells which express
neurotrophic factors may also promote survival of cells which
are predisposed to neurodegenerative disease, for example,
nigral tissue.44 The use of such cells to promote survival of
grafted tissue has also been suggested.45
Mechanical bridging is a physical necessity to support any
form of graft. Bridging may be cellular or by the use of artificial substances. The former will be enhanced by an appreciation of developmental neurobiology; the way in which
schwann cells or the immature nervous system provides a
permissive substance for cell growth. Much promise has been
shown recently with cells taken from the olfactory epithelium
(olfactory ensheathing cells; the only neuronal cells in the CNS
in which spontaneous axonal regeneration after sectioning
occurs) which may have the potential to guide regenerating
neurons. This has been demonstrated in both spinal cord (long
tract) and dorsal root ganglion experimental models.46±48
Evidence also exists that olfactory ensheathing cells may assist
regenerating axons in traversing injury-induced glial scar.49
Artificial substrates have the potential for repair of lesions
where bridging is required. The substrate required will ideally
be immune tolerant and have a porous scaffold. Vinyl chloride
porous tubes have been used experimentally in spinal cord
injury.50 Alginate gels soaked in neurotrophins have also been
suggested,51 and incorporation of guidance molecules discussed in the previous section could also be used.
Although the CNS has long been considered an immunologically privileged area, both cellular and humoral immune
responses may have a role to play in neuronal response to
injury. Although some investigators have suggested that the
immune response may assist regeneration, others have shown
that inhibition of TNF and TGF-b2 significantly decrease
scarring and tissue loss. Some interferons may modulate several extracellular matrix molecules and thus potentially
enhance axonal regeneration. Experimental evidence exists
that suggests that microglial cells, part of the central immune
response may act in a pro-regenerative role, possibly by way of
cytokine secretion. Possibly because the CNS is relatively
Journal of Clinical Neuroscience (2002) 9(6), 613±617
immunologically `privileged', rejection to cell transplants is
probably minimal.52
Neurotrophic factor and stem cell technology has applications in neurodegenerative and genetic diseases, neurotrauma
and cerebral ischaemia.53 Neurodegenerative diseases that are
amenable to treatment are most notably Parkinson's Disease
and Huntington's disease, by transplantation of cells genetically engineered to secrete l-dopa in the former condition and
stem cells into the head of the caudate nucleus in the latter.
Such treatment is still in its infancy. A number of genetic
diseases, such as mucopolysaccharidosis type VII may also be
treated by gene therapy techniques,54 the goal being to provide
a required protein or block one which is deleterious to normal
function. Various polyneuropathies (such as diabetic) may be
treated with neurotrophic factor delivery.55 ALS may also be
treated with intrathecal neurotrophic factor delivery.56 The
optimum method of neurotrophin delivery to give a prolonged
effect has not yet been established. The treatment of stroke and
head injury (especially secondary neurotrauma, similar to
stroke) is potentially treatable by transplantation of cells
genetically engineered to secrete neurotrophic factors or by
transplantation of stem cells. However, the widespread nature
of a cerebro-occlusive or cerebrotraumatic insult may lessen
the potential effect of a grafting procedure. Due to its focal
nature, spinal cord injury has long been a focus of neural
regenerative and repair and would involve a number of the
treatment aspects mentioned previously, such as cellular
replacement, axon support and guidance and removal of
inhibitory factors.57
CONCLUSION
Exciting advances are currently occurring in the field of neural
regeneration. An increased understanding of the nature of
neuronal injury, the factors which cause neuronal death and
inhibit neuronal regrowth, the way in which axons direct (and
redirect) themselves to a target and the role and actions of
neurotrophic factors have begun to hint at ways neuronal
injury can be treated more effectively clinically. The importance of developmental neurobiology has become increasingly
clear as the quest to appreciate the way in which the CNS
attempts to repair itself after injury is undertaken. Cellular
transplantation into the CNS is already a reality, and an
appreciation of aspects of CNS regeneration will assist in
augmenting this process. The introduction, survival and integration of new nerve cells into the damaged CNS remains the
ultimate goal.
ACKNOWLEDGEMENTS
The authors wish to thank Hiram Chipperfield, PhD student
at the Department of Anatomy and Developmental Biology,
The University of Queensland, for providing the photographs
used in this paper.
This work was supported by a grant from the Princess
Alexandra Hospital Research and Development Foundation.
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